Field of the Invention
The present invention relates in novel formulations of tellurium-containing compounds and particularly to tellurium-containing formulations that are designed for topical application. The novel formulation of tellurium-containing compounds of the present invention are characterized by chemical and physical stability, which is applicable when the tellurium-containing compounds are present therein in low, as well as in high, and very high concentrations.
Description of the Related Art
Various tellurium-containing compounds have been described in the art as having therapeutic activity. A particularly effective family of tellurium-containing compounds is taught, for example, in U.S. Pat. Nos. 4,752,614; 4,761,490; 4,764,461 and 4,929,739, whereby another effective family is taught, for example, in PCT International Patent Application No. PCT/IL2005/000989, which are all incorporated by reference as if fully set forth herein.
One of the most promising compounds described in these patents is ammonium trichloro(dioxyethylene-O,O′)tellurate, which is also referred to herein and in the art as AS101. AS101, as a representative example of the family of tellurium-containing compounds discussed hereinabove, exhibits antiviral (Nat. Immun. Cell Growth Regul. 7(3):163-8, 1988; AIDS Res Hum Retroviruses 8(5):613-23, 1992), and tumoricidal activity (Nature 330(6144):173-6, 1987; J. Clin. Oncol. 13(9):2342-53, 1995; J Immunol. 161(7):3536-42, 1998).
Another promising tellurium-containing compound is [TeO4(COCHH)2]2, which is also referred to herein and in the art as SAS.
SAS and other ditellurium-containing compounds have been shown to act as effective inhibitors of caspase-1/interleukin-1β enzyme b (ICE) and their use in various additional therapeutic applications have also been described (see, for example, PCT/IL2005/000989 supra).
It has been suggested that AS101, SAS, and other tellurium-containing compounds, act as immunomodulators that stimulate the innate and acquired arm of the immune response. For example, it has been shown that AS101 is a potent activator of interferon (IFN) in mice (J. Natl. Cancer Inst. 88(18):1276-84, 1996) and in humans (Nat. Immun. Cell Growth Regul. 9(3):182-90, 1990; Immunology 70(4):473-7, 1990; J. Natl. Cancer Inst. 88(18):1276-84, 1996). It has also been demonstrated that AS101, as well as other tellurium-containing immunomodulators, induce the secretion of a spectrum of cytokines, such as IL-1α, IL-6 and TNF-α, and that macrophages are one main target for AS101 (Exp. Hematol. 23(13):1358-66, 1995). It was further found that AS101 inhibits IL-10 at the m-RNA level, and that this inhibition may cause an increase in IL-12 and IFN-γ (Cell Immunol. 176(2):180-5, 1997; J. Natl. Cancer Inst. 88(18):1276-84, 1996).
Use of tellurium-containing compounds, such as AS101 and SAS, for treating conditions in which inhibition of ICE is beneficial has also been shown (see, for example, International Patent Application Nos. PCT/IL2005/000990 and PCT/IL2005/000989, supra). In another example, tellurium-containing compounds, in particular AS101, were shown to have a stimulating effect on bone marrow cells (U.S. Pat. No. 4,946,437).
Tellurium-containing compounds, in particular AS101, are further known to treat or prevent gastritis or peptic ulcer (U.S. Pat. No. 5,576,347), and to treat or prevent babesiosis, a tick-born disease (U.S. Pat. No. 5,610,179). AS101 has also been shown to have protective effects against lethal and sublethal effects of irradiation and chemotherapy (Blood 85: 1555, 1995; J. Nat. Cancer Inst. 88: 1276, 1996; In. J. Cancer 86: 281, 2000; J. Immunol. 156: 1101, 1996; J. Immunol. 145: 1507, 1990; Cancer Res. 51: 1499, 1991).
Additional examples of medical conditions that are treatable by AS101 and other tellurium-containing compounds are described, for example, in WO 2005/069735, U.S. Provisional Patent Application Nos. 60/716,924, 60/716,923, 60/610,660, in PCT International Application No. PCT/IL2005/000992, in WO 2005/060341, in U.S. patent application Ser. No. 11/226,375 and in U.S. Pat. Nos. 4,752,614, 4,761,490, 4,764,461 and 4,929,739 (supra).
Exemplary medical conditions that are known to be treatable by AS101 and other tellurium-containing compounds therefore include, for example, IL-1 mediated diseases, inflammatory diseases, autoimmune diseases, destructive bone disorders, proliferative disorders, infectious diseases, degenerative diseases, diseases associated with cell death, an excess dietary alcohol intake disease, retinal disorders, uveitis, inflammatory peritonitis, osteoarthritis, pancreatitis, asthma, adult respiratory distress syndrome, glomerulonephritis, rheumatoid arthritis, scleroderma, chronic thyroiditis, Grave's disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, chronic active hepatitis, myasthenia gravis, inflammatory bowel disease, Crohn's disease, psoriasis, atopic dermatitis, scarring, human papilloma virus related skin and mucosal membrane ailments, papilloma, condilloma, warts, alopecia and other conditions associated with hair loss, graft versus host disease, organ transplant rejection, organ apoptosis after burn injury, osteoporosis, leukemia's and related disorders, myelodysplastic syndrome, multiple myeloma-related bone disorders, acute myelogenous leukemia, chronic myelogenous leukemia, metastatic melanoma, basal cell carcinoma, actinic keratosis, UV skin damage, irradiation and chemotherapy-related effects, Kaposi's sarcoma, multiple myeloma, hemorrhagic shock, sepsis, septic shock, burns, Shigellosis, Alzheimer's disease, Huntington's disease, Kennedy's disease, prion diseases, cerebral ischemia, epilepsy, myocardial ischemia, acute and chronic heart diseases, myocardial infarction, congestive heart failure, atherosclerosis, coronary artery bypass graft, spinal muscular atrophy, amyotrophic lateral sclerosis, multiple sclerosis, HIV-related encephalitis, aging, neurological damage due to stroke, ulcerative colitis, peptic ulcer, traumatic brain injury, spinal cord injury, hepatitis-B, hepatitis-C, hepatitis-G, yellow fever, dengue fever, or Japanese encephalitis, various forms of liver disease, renal disease, polycystic kidney disease, H. pylori-associated gastric and duodenal ulcer disease, HIV infection, tuberculosis, immunotherapy for the treatment of various forms of cancer, babesiosis, organ failure, meningitis and complications associated with coronary artery bypass grafts.
AS101 is also characterized by low toxicity, with the LD50 values in rats following intravenous and intramuscular administration of AS101 are 500-1000 folds higher than the immunologically effective dose. AS101 is therefore considered as an attractive therapeutically active agent.
Topical application of tellurium-containing compounds and pharmaceutical compositions thereof, has been found effective in the treatment of various skin-related diseases and disorders.
Thus, tellurium-containing compounds were found exceptionally effective in treating skin and mucosal membrane ailments, caused by human papilloma viruses (HPV) (see, for example WO 2005/069735, supra). HPV is a very common virus that causes abnormal cells or growth of tissue on the skin of the body, thus causing abnormal tissue changes on the feet, hands, vocal cords, mouth and genital (sex) organs.
Another topical use of tellurium-containing compounds is in the treatment or prevention of alopecia and other conditions associated with hair loss (see for example, U.S. Provisional Patent Application No. 60/610,660, supra, U.S. Pat. Nos. 6,552,089 and 5,262,149). In human clinical studies (FASEB J 18: 400-402, 2004), AS101 exhibited the ability to protect cancer patients from both bone marrow toxicity and alopecia induced by chemotherapy. AS101 has been found to induce hair growth in nude mice, normal mice, and in humans. In nude mice, AS101 has been shown to exert this effect when applied systemically, orally or topically.
Other skin conditions which may be treated by topical application of tellurium-containing compounds, include basal cell carcinoma (BCC), actinic keratosis (AK) (U.S. Provisional Patent Application No. 60/716,923, supra), damages caused by exposure to UV irradiation (U.S. Provisional Patent Application No. 60/716,924, supra), psoriasis (U.S. Pat. No. 6,472,381), atopic dermatitis (also known as eczema), Kaposi's sarcoma, scleroderma, burns, scarring (see U.S. Provisional Patent Application No. 60/610,660) and metastatic melanoma (Sun et al. “Anticarcinoma activity of a novel drug, 3-ethyl-3′-methyl-thiatelluracarbocyanine iodide (Te), a tellurium-containing cyanine targeted at mitochondria”, Clinical Cancer Research, 1996, Vol 2, Issue 8, 1335-1340).
As is widely recognized in the art, pharmaceutical compositions for topical application typically include a relatively large concentration of the applied active ingredient.
While studying the features required for a tellurium-containing compound to exhibit a therapeutic activity, it has been found that organic and inorganic tellurium-containing compounds that are derived from tellurium dioxide and hence have one or more tellurium dioxo moieties are highly potent as therapeutically active agents.
Such tellurium-containing compounds are known to exhibit an oxidative potential and, under certain conditions, may be considered unstable, both physically and chemically. When formulated into pharmaceutical compositions, and particularly for topical application, in which their concentration is relatively high, compounds containing tellurium dioxo moieties may be involved in oxidation and other reactions, which may lead, for example, to coloration of the pharmaceutical composition, degradation of various components therein, and/or incompatibility with certain packaging materials. A particular disadvantage of such tellurium dioxo-containing compounds is seen when compositions containing same are packaged, or come in other contact, with metallic substances. Metals such as aluminum are rapidly oxidized by these compounds. Therefore, to date, tellurium-containing pharmaceutical compositions, which are intended for topical application, often include relatively low concentrations of the active ingredient.
Additional limitations associated with formulating active tellurium-containing compounds into compositions for topical application results from the relatively poor solubility of compounds such as AS101 and SAS in aqueous or oleaginous carriers. While some topical formulations are based on oils and other hydrophobic carriers, formulations that are based on aqueous or amphiphilic carriers are beneficially characterized by usage convenience, being easily applied, non-greasy, and particularly washable.
Pharmaceutical compositions of tellurium-containing compounds and various carriers have been described, for example, in International Patent Application Nos. PCT/IL2005/000990 and PCT/IL2005/000989 and U.S. Pat. Nos. 4,752,614; 4,761,490, 4,764,461 and 4,929,739 (supra). Amongst the various carriers cited therein, carriers comprising polyethylene glycol (PEG) have been mentioned in passing. However, the applicability of PEG-based tellurium-containing formulations for topical uses, as well as the chemical and physical stability of such formulations, have never been established nor practiced heretofore.
In view of the exceptional therapeutic characteristics of tellurium-containing compounds which are derived from tellurium dioxide and hence have one or more tellurium dioxo moieties, described hereinabove, there is a widely recognized need for, and it would be highly advantageous to have, stable tellurium-containing formulations for topical application.